High expression of STAT3 within the tumour-associated stroma predicts poor outcome in breast cancer patients.

INTRODUCTION: Triple-negative breast cancer (TNBC) patients have the poorest clinical outcomes compared to other molecular subtypes of breast cancer. IL6/JAK/STAT3 signalling is upregulated in breast cancer; however, there is limited evidence for its role in TNBC. This study aimed to assess the expression of IL6/JAK/STAT3 in TNBC as a prognostic biomarker. METHODS: Tissue microarrays consisting of breast cancer specimens from a retrospective cohort (n = 850) were stained for IL6R, JAK1, JAK2 and STAT3 via immunohistochemistry. Staining intensity was assessed by weighted histoscore and analysed for association with survival/clinical characteristics. In a subset of patients (n = 14) bulk transcriptional profiling was performed using TempO-Seq. Nanostring GeoMx® digital spatial profiling was utilised to establish the differential spatial gene expression in high STAT3 tumours. RESULTS: In TNBC patients, high expression of stromal STAT3 was associated with reduced cancer-specific survival (HR = 2.202, 95% CI: 1.148-4.224, log rank p = 0.018). TNBC patients with high stromal STAT3 had reduced CD4+ T-cell infiltrates within the tumour (p = 0.001) and higher tumour budding (p = 0.003). Gene set enrichment analysis (GSEA) of bulk RNA sequencing showed high stromal STAT3 tumours were characterised by enrichment of IFNγ, upregulation of KRAS signalling and inflammatory signalling Hallmark pathways. GeoMx™ spatial profiling showed high stromal STAT3 samples. Pan cytokeratin (panCK)-negative regions were enriched for CD27 (p < 0.001), CD3 (p < 0.05) and CD8 (p < 0.001). In panCK-positive regions, high stromal STAT3 regions had higher expression of VEGFA (p < 0.05). CONCLUSION: High expression of IL6/JAK/STAT3 proteins was associated with poor prognosis and characterised by distinct underlying biology in TNBC.

Prognostic role of preoperative circulating systemic inflammatory response markers in primary breast cancer: meta-analysis.

BACKGROUND: Circulating markers of the systemic inflammatory response are prognostic in several cancers, but their role in operable breast cancer is unclear. A systematic review and meta-analysis of the literature was carried out. METHODS: A search of electronic databases up to August 2020 identified studies that examined the prognostic value of preoperative circulating markers of the systemic inflammatory response in primary operable breast cancer. A meta-analysis was carried out for each marker with more than three studies, reporting a HR and 95 per cent confidence interval for disease-free survival (DFS), breast cancer-specific survival (BCSS) or overall survival (OS). RESULTS: In total, 57 studies were reviewed and 42 were suitable for meta-analysis. Higher neutrophil-to-lymphocyte ratio (NLR) was associated with worse overall survival (OS) (pooled HR 1.75, 95 per cent c.i. 1.52 to 2.00; P < 0.001), disease-free survival (DFS) (HR 1.67, 1.50 to 1.87; P < 0.001), and breast cancer-specific survival (BCSS) (HR 1.89, 1.35 to 2.63; P < 0.001). This effect was also seen with an arithmetically-derived NLR (dNLR). Higher platelet-to-lymphocyte ratio (PLR) was associated with worse OS (HR 1.29, 1.10 to 1.50; P = 0.001) and DFS (HR 1.58, 1.33 to 1.88; P < 0.001). Higher lymphocyte-to-monocyte ratio (LMR) was associated with improved DFS (HR 0.65, 0.51 to 0.82; P < 0.001), and higher C-reactive protein (CRP) level was associated with worse BCSS (HR 1.22, 1.07 to 1.39; P = 0.002) and OS (HR 1.24, 1.14 to 1.35; P = 0.002). CONCLUSION: Current evidence suggests a role for preoperative NLR, dNLR, LMR, PLR, and CRP as prognostic markers in primary operable breast cancer. Further work should define their role in clinical practice, particularly reproducible thresholds and molecular subtypes for which these may be of most value.

Antibiotic prophylaxis in breast cancer surgery (PAUS trial): randomised clinical double-blind parallel-group multicentre superiority trial.

BACKGROUND: Participants were patients with invasive breast cancer undergoing primary surgery. The aim was to test whether a single dose of amoxicillin-clavulanic acid would reduce wound infection at 30 days postoperatively, and to identify risk factors for infection. METHODS: Participants were randomised to either a single bolus of 1.2 g intravenous amoxicillin-clavulanic acid after the induction of anaesthesia (intervention) or no antibiotic (control). The primary outcome was the incidence of wound infection at 30 days postoperatively. RESULTS: There were 871 evaluable patients. Of these, 438 received prophylactic antibiotic and 433 served as controls. Seventy-one (16.2 per cent) patients in the intervention group developed a wound infection by 30 days, while there were 83 (19.2 per cent) infections in the control group. This was not statistically significant (odds ratio (OR) 0.82, 95 per cent c.i. 0.58 to 1.15; P = 0.250). The risk of infection increased for every 5 kg/m2 of BMI (OR 1.29, 95 per cent c.i. 1.10 to 1.52; P = 0.003). Patients who were preoperative carriers of Staphylococcus aureus had an increased risk of postoperative wound infection; however, there was no benefit of preoperative antibiotics for patients with either a high BMI or who were carriers of S. aureus. CONCLUSION: There was no statistically significant or clinically meaningful reduction in wound infection at 30 days following breast cancer surgery in patients who received a single dose of amoxicillin-clavulanic acid preoperatively. REGISTRATION NUMBER: N0399145605 (National Research Register).

There is little research about antibiotics in breast cancer surgery. Surgeons are not certain whether or not to use antibiotics for their patients. The aim of the Prophylactic Antibiotic Use in Surgery (PAUS) trial was to ask a question, 'Do preoperative antibiotics have any benefit for patients having surgery for breast cancer?' In the PAUS trial patients were given information to decide whether they wished to take part in the trial or not. Participants were randomly placed in one of two groups. Half were given one dose of the amoxicillin­clavulanic acid antibiotic at the time of their operation. The other half had no antibiotic. Neither the patient nor the surgeon knew which group the patient was in. Patients were carefully checked until 30 days after their operation for signs of wound infection. Altogether, 871 patients agreed to take part in the PAUS trial. Of these, 438 patients had the antibiotic and 433 had no antibiotic. The PAUS trial showed that there was no difference in the number of wound infections when comparing the two groups. Seventy-one patients (16.2 per cent) who had been given the antibiotic developed a wound infection by 30 days versus 83 (19.2 per cent) in the group who had not been given the antibiotic. This trial shows that antibiotics may not be needed for breast cancer surgery. PAUS may help to cut down on unnecessary antibiotic use.

Retrospective, Multicenter Analysis Comparing Conventional with Oncoplastic Breast Conserving Surgery: Oncological and Surgical Outcomes in Women with High-Risk Breast Cancer from the OPBC-01/iTOP2 Study.

INTRODUCTION: Recent data suggest that margins ≥2 mm after breast-conserving surgery may improve local control in invasive breast cancer (BC). By allowing large resection volumes, oncoplastic breast-conserving surgery (OBCII; Clough level II/Tübingen 5-6) may achieve better local control than conventional breast conserving surgery (BCS; Tübingen 1-2) or oncoplastic breast conservation with low resection volumes (OBCI; Clough level I/Tübingen 3-4). METHODS: Data from consecutive high-risk BC patients treated in 15 centers from the Oncoplastic Breast Consortium (OPBC) network, between January 2010 and December 2013, were retrospectively reviewed. RESULTS: A total of 3,177 women were included, 30% of whom were treated with OBC (OBCI n = 663; OBCII n = 297). The BCS/OBCI group had significantly smaller tumors and smaller resection margins compared with OBCII (pT1: 50% vs. 37%, p = 0.002; proportion with margin <1 mm: 17% vs. 6%, p < 0.001). There were significantly more re-excisions due to R1 ("ink on tumor") in the BCS/OBCI compared with the OBCII group (11% vs. 7%, p = 0.049). Univariate and multivariable regression analysis adjusted for tumor biology, tumor size, radiotherapy, and systemic treatment demonstrated no differences in local, regional, or distant recurrence-free or overall survival between the two groups. CONCLUSIONS: Large resection volumes in oncoplastic surgery increases the distance from cancer cells to the margin of the specimen and reduces reexcision rates significantly. With OBCII larger tumors are resected with similar local, regional and distant recurrence-free as well as overall survival rates as BCS/OBCI.

Extreme Oncoplasty: Breast Conservation in Patients with Large, Multifocal, and Multicentric Breast Cancer.

INTRODUCTION: Extreme Oncoplastic Breast Conservation Surgery (EOBCS) is offered in selected patients with multifocal or multicentric breast cancer (MFMC). Recent evidence has suggested that EOBCS may be a valuable resource for patients with MFMC who may avoid the risk associated with mastectomy in favour of the benefits of breast conservation without risking their oncological outcomes. Our study examined the practice of EOBCS in two regional breast units in Glasgow, United Kingdom. MATERIALS AND METHODS: A prospectively collected database of 50 patients treated with EOBC in two breast units in Glasgow between 2007 and 2018 were evaluated, and clinical outcomes were observed. RESULTS: Fifty patients (median age 55) underwent EOBCS, of which 43 (86%) had invasive disease. Median tumour size was 55mm (50-90) and multifocal disease was identified in 22 (44%) patients. Nine patients (18%) were found to have positive margins and underwent a second procedure, with 6 (12%) proceeding to mastectomy. Five-year disease free survival rate was 91.5%, while cancer-specific survival was 95.7%. CONCLUSION: EOBCS is oncologically safe in short-term follow-up. Large scale studies are required to confirm these preliminary results, in order to offer EOBCS as a valid option to patients with advanced or multifocal breast cancer.

Variation in the management of elderly patients in two neighboring breast units is due to preferences and attitudes of health professionals.

Introduction: Elderly breast cancer patients have been shown to be managed less aggressively than younger patients. There is evidence that their management varies between institutions. We audited the management of elderly patients in two neighboring units in Glasgow and aimed to identify reasons for any differences in practice found. Methods: Patients aged ≥70 years, who were managed for a new diagnosis of breast cancer in the two units between 2009 and 2013, were identified from a prospectively maintained database. Tumor pathology, treatment details, postcode and consultant in charge of care were obtained from the same database. Comorbidities were obtained from each patient's electronic clinical record. Questionnaires were distributed to members of each multidisciplinary teams. Results: 487 elderly patients in Unit 1 and 467 in Unit 2 were identified. 76.2% patients in Unit 1 were managed surgically compared to 63.7% in Unit 2 (p<0.0001). There was no difference between the two units in patient age, tumor pathology, deprivation or comorbidity. 16.2% patients managed surgically in Unit 1 had a comorbidity score of 6 and above compared to 11% of surgically managed patients in Unit 2 (p=0.036). Responses to questionnaires suggested that staff at Unit 1 were more confident of the safety of general anesthetic in elderly patients and were more willing to consider local anesthetic procedures. Conclusion: A higher proportion of patients aged >70 years with breast cancer were managed surgically in Unit 1 compared to Unit 2. Reasons for variation in practice seem to be related to attitudes of medical professionals toward surgery in the elderly, rather than patient or pathological factors.

Oncoplastic breast conservation occupies a niche between standard breast conservation and mastectomy - A population-based prospective audit in Scotland.

INTRODUCTION: The role of oncoplastic breast conservation (OBC) surgery is not fully defined in terms of whether it is equivalent to standard breast conservation (SBC), or more an alternative to mastectomy, or whether it occupies its own niche somewhere between the two. Therefore, we have carried out a population-based prospective audit of the current OBC practice in Scotland. METHODS: All patients diagnosed with breast cancer in the whole of Scotland between 01/01/2014 and 31/12/2015 were prospectively recorded within the National Managed Clinical Networks databases. Patients treated with OBC were compared to patients who had SBC, mastectomy and mastectomy with immediate reconstruction (MIR). RESULTS: 8075 patients were included (OBC:217(2.7%); SBC:5241(64.9%); mastectomy:1907(23.6%); MIR:710(8.8%)). OBC patients were younger than SBC or mastectomy, but older than MIR (p < 0.0001). OBC patients were between SBC and mastectomy patients in terms of clinical and pathological tumour size (all p < 0.001), rates of lobular cancers (v.SBC:p = 0.015 and v.mastectomy:p < 0.001), high-grade tumours (v.SBC:p = 0.030 and v.mastectomy:p = 0.008), ER negative (v.SBC: p = 0.042) and HER-2 positive (v.SBC: p = 0.003) tumours, and nodal metastasis (v.mastectomy: p < 0.001). More OBC patients received (neo)adjuvant chemo- and hormonal therapy (p ≤ 0.001), adjuvant radiotherapy (p = 0.005), trastuzumab (p < 0.001) than SBC. More OBC patients presented through screening (v.mastectomy/MIR: p < 0.0001). Time to surgery from diagnosis was longer for OBC than SBC/mastectomy (p < 0.0001), but shorter than MIR (p = 0.007). CONCLUSION: This national audit demonstrates that OBC occupies its own niche between SBC, mastectomy and MIR in the surgical treatment of breast cancer in Scotland. We recommend that OBC should be recorded separately in other national breast cancer registries.

The role of gamma delta T lymphocytes in breast cancer: a review.

Gammadelta T (γδT) lymphocytes have provoked interest in oncology, particularly as regards their potential use in immunotherapy, because of their unique ability to recognise antigens without a requirement for major histocompatibility complex antigen presentation, and to quickly activate an anti-tumour response. However, work in some cancers has suggested that they also have pro-tumourigenic activity. Their role in breast cancer is unclear. This review outlines the evidence to date in in vitro studies, in vivo mouse models and in human studies regarding the role of γδT lymphocytes in breast cancer. We describe the seemingly opposing roles of the predominantly circulating Vγ9Vδ2+ subtype, which can suppress tumour growth through direct cytotoxicity, induction of apoptosis and inhibition of angiogenesis, and the predominantly tumour-infiltrating γδ1+ subtype which can promote tumour growth and spread through immunosuppressant effects. We summarise the evidence in breast cancer for the mechanisms of action of γδT lymphocytes and describe how factors in the tumour microenvironment may affect their function, polarising them towards a pro-tumourigenic, immune-suppressing role. We also describe the experience to date of γδT lymphocytes in immunotherapy for breast cancer and suggest the direction of work going forward, particularly as regards different breast cancer subtypes.

A population-based audit of surgical practice and outcomes of oncoplastic breast conservations in Scotland - An analysis of 589 patients.

INTRODUCTION: Current evidence for oncoplastic breast conservation (OBC) is based on single institutional series. Therefore, we carried out a population-based audit of OBC practice and outcomes in Scotland. METHODS: A predefined database of patients treated with OBC was completed retrospectively in all breast units practicing OBC in Scotland. RESULTS: 589 patients were included from 11 units. Patients were diagnosed between September 2005 and March 2017. High volume units performed a mean of 19.3 OBCs per year vs. low volume units who did 11.1 (p = 0.012). 23 different surgical techniques were used. High volume units offered a wider range of techniques (8-14) than low volume units (3-6) (p = 0.004). OBC was carried out as a joint operation involving a breast and a plastic surgeon in 389 patients. Immediate contralateral symmetrisation rate was significantly higher when OBC was performed as a joint operation (70.7% vs. not joint operations: 29.8%; p < 0.001). The incomplete excision rate was 10.4% and was significantly higher after surgery for invasive lobular carcinoma (18.9%; p = 0.0292), but was significantly lower after neoadjuvant chemotherapy (3%; p = 0.031). 9.2% of patients developed major complications requiring hospital admission. Overall the complication rate was significantly lower after neoadjuvant chemotherapy (p = 0.035). The 5 year local recurrence rate was 2.7%, which was higher after OBC for DCIS (8.3%) than invasive ductal cancer (1.6%; p = 0.026). 5-year disease-free survival was 91.7%, overall survival was 93.8%, and cancer-specific survival was 96.1%. CONCLUSION: This study demonstrated that measured outcomes of OBC in a population-based multi-centre setting can be comparable to the outcomes of large volume single centre series.

'Care left undone' during nursing shifts: associations with workload and perceived quality of care.

BACKGROUND: There is strong evidence to show that lower nurse staffing levels in hospitals are associated with worse patient outcomes. One hypothesised mechanism is the omission of necessary nursing care caused by time pressure-'missed care'. AIM: To examine the nature and prevalence of care left undone by nurses in English National Health Service hospitals and to assess whether the number of missed care episodes is associated with nurse staffing levels and nurse ratings of the quality of nursing care and patient safety environment. METHODS: Cross-sectional survey of 2917 registered nurses working in 401 general medical/surgical wards in 46 general acute National Health Service hospitals in England. RESULTS: Most nurses (86%) reported that one or more care activity had been left undone due to lack of time on their last shift. Most frequently left undone were: comforting or talking with patients (66%), educating patients (52%) and developing/updating nursing care plans (47%). The number of patients per registered nurse was significantly associated with the incidence of 'missed care' (p<0.001). A mean of 7.8 activities per shift were left undone on wards that are rated as 'failing' on patient safety, compared with 2.4 where patient safety was rated as 'excellent' (p < 0.001). CONCLUSIONS: Nurses working in English hospitals report that care is frequently left undone. Care not being delivered may be the reason low nurse staffing levels adversely affects quality and safety. Hospitals could use a nurse-rated assessment of 'missed care' as an early warning measure to identify wards with inadequate nurse staffing.

Measuring relational aspects of hospital care in England with the 'Patient Evaluation of Emotional Care during Hospitalisation' (PEECH) survey questionnaire.

OBJECTIVES: To first, validate in English hospitals the internal structure of the 'Patient Evaluation of Emotional Care during Hospitalisation' (PEECH) survey tool which was developed in Australia and, second, to examine how it may deepen the understanding of patient experience through comparison with results from the Picker Patient Experience Questionnaire (PPE-15). DESIGN: A 48-item survey questionnaire comprising both PEECH and PPE-15 was fielded. We performed exploratory factor analysis and then confirmatory factor analysis using a number of established fit indices. The external validity of the PEECH factor scores was compared across four participating services and at the patient level, factor scores were correlated with the PPE-15. SETTING: Four hospital services (an Emergency Admissions Unit; a maternity service; a Medicine for the Elderly department and a Haemato-oncology service) that contrasted in terms of the reported patient experience performance. PARTICIPANTS: Selection of these acute service settings was based on achieving variation of the following factors: teaching hospital/district general hospital, urban/rural locality and high-performing/low-performing organisations (using results of annual national staff and patient surveys). A total of 423 surveys were completed by patients (26% response rate). RESULTS: A different internal structure to the PEECH instrument emerged in English hospitals. However, both the existing and new factor models were similar in terms of fit. The correlations between the new PEECH factors and the PPE-15 were all in the expected direction, but two of the new factors (personal interactions and feeling valued) were more strongly associated with the PPE-15 than the remaining two factors (feeling informed and treated as an individual). CONCLUSIONS: PEECH can help to build an understanding of complex interpersonal aspects of quality of care, alongside the more transactional and functional aspects typically captured by PPE-15. Further testing of the combined instrument should be undertaken in a wider range of healthcare settings.